Venetoclax Shows Efficacy In Refractory 17p[del] CLL

Hard to treat chronic lymphocytic leukaemia patients with a chromosome 17p deletion may benefit from the BCL2 inhibitor venetoclax

medwireNews: Venetoclax is active and well tolerated for the treatment of relapsed or refractory chromosome 17p deletion (del[17p]) chronic lymphocytic leukaemia (CLL), phase II trial investigators suggest.

The oral, selective BCL2 inhibitor, which induces apoptosis independently of p53, was tested in 107 patients, beginning at a weekly dose of 20 mg and increasing to 400 mg over 4 to 5 weeks, followed by 400 mg/day until disease progression or discontinuation for other reasons.

After a median of 12.1 months, the primary endpoint of overall response, defined as a partial remission or better, was achieved by 79.4% of the patients, report Stephan Stilgenbauer, from Ulm University in Germany, and co-authors.

Independent review reported a complete remission or complete remission but incomplete recovery of blood counts in 8%, a nodular partial remission in 3%, and a partial remission in 69%. And 21% of patients had stable or progressive disease.

In addition, 18 of 45 patients who were assessed for peripheral blood minimal residual disease had no detectable disease and bone marrow results for 10 of these patients found no minimal residual disease in six.

Exploratory subanalyses suggested that response was not significantly associated with treatment refractory-disease, proportion of CLL cells with the 17q[del] or other negative prognostic markers, the researcher write in The Lancet Oncology.

The estimated 12-month progression-free survival and overall survival rates were 72.0% and 86.7% with an estimated 85.0% of responders continuing to do so after 12 months.

Neutropenia, infection, anaemia and thrombocytopenia were the most common grade 3 or 4 side effects, affecting 40%, 20%, 18% and 15% of patients, respectively. Neutropenia led to dose interruption or reduction in 5% and 4% of patients, respectively. Serious infections included pneumonia (6%) and lower and upper respiratory tract infection (2% both), with one death from septic shock; venetoclax interruption or dose reduction occurred in 9% and 2%, respectively.

The author of an accompanying comment notes that although the majority of patients had received immunochemotherapy, just five had previously received kinase inhibitor therapy whereas most CLL patients are now treated with ibrutinib or idelalisib.

“[T]he population studied might not have been completely representative of the typical patient population with relapsed or refractory and TP53-disrupted chronic lymphocytic leukaemia that hemato-oncologists will have to treat in the future”, writes Davide Rossi, from Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research in Bellinzona.

“Although this aspect might represent a limitation, the study provides the proof of concept that venetoclax is active even in TP53-defective tumours that are resistant to kinase inhibitors, thus prompting clinical trials (ie, NCT02141282) with venetoclax in this ultra-high-risk disease category.”

Observing that kinase inhibitors seem to be more active in lymph nodes while venetoclax appears to be most active in the blood and bone marrow, he concludes: “The idea that chronic lymphocytic leukaemia cells can be mobilised from tissues into the bloodstream by kinase inhibitors and killed in the blood by venetoclax provides a strong rationale for studies that test these novel agents in sequence or in combination.”

Reference

Stilgenbauer S, Eichhorst B, Schtelig J, et al. Venteoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016; Advance online publication 10 May. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30019-5

Rossi D. Venteoclax: a new weapon to treat high-risk CLL. Lancet Oncol 2016; Advance online publication 10 May. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30100-0

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